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    Clinical Trial Results:
    Phase I/II Study combining humanised anti-CD20 (veltuzumab), anti-CD22 (epratuzumab) and both monoclonal antibodies with chemotherapy in adults with recurrent B precursor acute lymphoblastic leukaemia (ALL)- MARALL

    Summary
    EudraCT number
    2008-002286-32
    Trial protocol
    GB  
    Global end of trial date
    10 Oct 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Sep 2017
    First version publication date
    08 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    6125
    Additional study identifiers
    ISRCTN number
    ISRCTN15257573
    US NCT number
    NCT01279707
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Barts Health NHS Trust
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    CECM Trials Team, Queen Mary University of London, 0044 02078828197, bci-cecmmonitoring@qmul.ac.uk
    Scientific contact
    CECM Trials Team, Queen Mary University of London, 0044 02078828197, bci-cecmmonitoring@qmul.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to assess the safety and tolerability of the combination of veltuzumab and /or epratuzumab with chemotherappy for recurrent adult B-precursor acute lymphoblastic leukaemia
    Protection of trial subjects
    Patients will be pre-medicated with chlorphenamine and paracetamol as per local policy, before the start of each antibody infusion, in order to minimise infusional toxicity (hypersensitivity). Patients will be pre-medicated with chlorphenamine (10mg IV) and paracetamol (1g PO), 30-60 minutes prior to the start of each antibody infusion in order to minimise hypersensitivity (if two antibodies are given only one dose of chlorphenamine and paracetamol is needed).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Dec 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    21
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Starting in December 2010, 29 patients were recruited in total to the study, of which 26 met the criteria for evaluable. The study followed a parallel 3+3 design in phase 1 of the study (Cohort A and B). Subsequently, a third cohort (Cohort C) received the combination of antibodies with induction chemotherapy.

    Pre-assignment
    Screening details
    Inclusion criteria included patients with confirmed diagnosis of recurrent or refractory B-precursor ALL. 29 patients were screened, however only 26 completed study treatment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort A - Veltuzumab and Re-induction chemotherapy
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    veltuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Veltuzumab with induction chemotherapy. Veltuzumab will be administered at 200mg/m2 IV on Day 8 and subsequently, (if tolerated on Day 8), on Days 15, 22, 29.

    Arm title
    Cohort B - Epratuzumab + re-induction chemotherapy
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Epratuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epratuzumab with induction chemotherapy. Epratuzumab will be administered at 360mg/m2 IV on Days 8, 15, 22 and 29.

    Arm title
    Cohort C - Veltuzumab and Epratuzumab + induction chemotherapy
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    veltuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epratuzumab + Veltuzumab with induction chemotherapy. Epratuzumab will be administered at 360mg/m2 IV on Days 8, 15, 22 and 29. Veltuzumab will be administered at 200mg/m2 IV on Day 8, 15, 22 and 29. Veltuzumab will be infused immediately after the infusion of epratuzumab.

    Investigational medicinal product name
    Epratuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epratuzumab + Veltuzumab with induction chemotherapy. Epratuzumab will be administered at 360mg/m2 IV on Days 8, 15, 22 and 29. Veltuzumab will be administered at 200mg/m2 IV on Day 8, 15, 22 and 29. Veltuzumab will be infused immediately after the infusion of epratuzumab.

    Number of subjects in period 1
    Cohort A - Veltuzumab and Re-induction chemotherapy Cohort B - Epratuzumab + re-induction chemotherapy Cohort C - Veltuzumab and Epratuzumab + induction chemotherapy
    Started
    3
    3
    21
    Completed
    3
    3
    20
    Not completed
    0
    0
    1
         Patient died before assessment
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A - Veltuzumab and Re-induction chemotherapy
    Reporting group description
    -

    Reporting group title
    Cohort B - Epratuzumab + re-induction chemotherapy
    Reporting group description
    -

    Reporting group title
    Cohort C - Veltuzumab and Epratuzumab + induction chemotherapy
    Reporting group description
    -

    Reporting group values
    Cohort A - Veltuzumab and Re-induction chemotherapy Cohort B - Epratuzumab + re-induction chemotherapy Cohort C - Veltuzumab and Epratuzumab + induction chemotherapy Total
    Number of subjects
    3 3 21 27
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    3 3 15 21
        From 65-84 years
    0 0 6 6
    Age continuous
    Units: years
        median (full range (min-max))
    23 (21 to 49) 31 (21 to 57) 51 (22 to 76) -
    Gender categorical
    Units: Subjects
        Female
    0 0 11 11
        Male
    3 3 7 13
        Unknown
    0 0 3 3
    ECOG Performance Status
    Units: Subjects
        ECOG 2
    1 0 3 4
        ECOG 0 or 1
    2 3 16 21
        ECOG Unknown
    0 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Cohort A - Veltuzumab and Re-induction chemotherapy
    Reporting group description
    -

    Reporting group title
    Cohort B - Epratuzumab + re-induction chemotherapy
    Reporting group description
    -

    Reporting group title
    Cohort C - Veltuzumab and Epratuzumab + induction chemotherapy
    Reporting group description
    -

    Primary: Dose Limiting Toxicity

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    End point title
    Dose Limiting Toxicity [1]
    End point description
    The primary endpoint of the study is safety, measured by the number of dose-limiting toxicities (DLTs) and tolerability of both veltuzumab and epratuzumab given in combination with ALL reinduction chemotherapy
    End point type
    Primary
    End point timeframe
    Assessment at day 29
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Dose Limiting Toxicity is a count data and hence no statistics are needed
    End point values
    Cohort A - Veltuzumab and Re-induction chemotherapy Cohort B - Epratuzumab + re-induction chemotherapy Cohort C - Veltuzumab and Epratuzumab + induction chemotherapy
    Number of subjects analysed
    3
    3
    20
    Units: number/percentage
    0
    0
    4
    No statistical analyses for this end point

    Secondary: Complete Remission (CR) Rate

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    End point title
    Complete Remission (CR) Rate [2]
    End point description
    The complete remission (CR) rate – assessed by morphological CR on a bone marrow taken at Day 29 of therapy or at the commencement of count recovery.
    End point type
    Secondary
    End point timeframe
    Measured at Day 29 of therapy or at the commencement of count recovery.
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary endpoint is based on cohort C (combination arm) and hence complete remission rate is reported only for cohort C.
    End point values
    Cohort C - Veltuzumab and Epratuzumab + induction chemotherapy
    Number of subjects analysed
    20
    Units: Percentage
        number (confidence interval 95%)
    40 (19 to 61)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From consent to 30 days post last dose of IMP
    Adverse event reporting additional description
    Only Grade treatment-related 3/4 AE are reported here
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Cohort C
    Reporting group description
    -

    Serious adverse events
    Cohort C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 21 (66.67%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    1
    Injury, poisoning and procedural complications
    Fractured Rib
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Vasovagal Episode
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PICC Line Thrombus
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Splenic subcapsular infarct
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Liver Toxicity
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rise in GGT levels
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Raised CRP hypophataemia, hypokalemia, anemia and phrombolytopenia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Raised LFTs- Liver failure
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Asymptotic bradycardia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Blood and lymphatic system disorders
    Febrile post epratuzumab and veltuzumab infusion
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death due to relapse of ALL
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Rigors and increased temperature 39.3C
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Nausea and Vomitting
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation, Dehydration, Nausea and vomiting
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Neutropenic sepsis
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Chest infection with fever
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 21 (76.19%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    1
    Platelet count decreased
         subjects affected / exposed
    8 / 21 (38.10%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    1
    Anaemia
         subjects affected / exposed
    6 / 21 (28.57%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyper-glycaemia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2010
    • Exclude patients with Philadelphia positive (Ph +ve) ALL • Native E. coli asparaginase replaced by Oncaspar, a peglated form of L-asparaginase with fewer side effects.
    08 Sep 2010
    • Inclusion of patients who have had more than one relapse of their leukaemia • Inclusion of patients who are philadelphia positive (Ph+ve) who have failed previous treatment with TK1 • Inclusion of patients who have had prior mediastinal radiotherapy • Changes to Principal Investigators and sites
    08 Sep 2010
    change from intensive to less intensive chemotherapy removal of daunorubicin; removal of cardiac MRI and ECG; removal of upper age limit; inclusion of patients who have had more than one relapse; inclusion of patients who have had prior radiotherapy Change of CI: Prof. Andrew Lister to Prof. Matthew Smith
    01 Feb 2011
    • Changes to Principal Investigators and sites
    01 Feb 2011
    -Amended timeframe of lumbar puncture and bone marrow samples during screening and addition of collection of bone marrow for research at screening, -Extended study duration, Inclusion of refractory patients, reduce time limit since previous antibody therapy, -Addition of new sites
    22 Sep 2011
    • Changes to inclusion criteria  Include refractory patients.  Amend the current definition of refractory patients.  Requirement that patients should have greater than or equal to 5% blasts in the marrow. • Changes to exclusion criteria  Allowing patients to have received corticosteroids for the current relapse episode for a maximum of 10 days rather than 5.  Positive antinuclear antibody (ANA) test.  Change of exclusion of patient receiving antibody therapy in the last 9 months to last 3 months in line with recommendations from Immunomedics. • Addition of ANA testing to study schedule and medical examinations and laboratory assessments at screening and Day 29 • Removal of option to provide peripheral blood rather than bone marrow for the MRD test in this protocol to make bone marrow an absolute requirement. • Changes to preparation and administration of Veltuzumab and epratuzumab in line with new administration guidelines from Manufacturer (Immunomedics). • Removal of IMP status of Vincristine, PEG-Asparaginase (OncasparR), Dexamethasone, Methotrexate and Erwinia Asparaginase (ErwinaseR) (now NIMPs) which are standard chemotherapy for ALL patients. • Change to timing of administration of pre-medication from 15-30mins to 30-60mins before administration of epratuzumab or veltuzumab to reduce risk of hypersensitivity in line with Immunomedics guidelines. • Change of Route of administration of PEG-Aspariginase from IV to IV or IM to ensure consistency in protocol document and in line with SmPC.
    22 Sep 2011
    Changes to inclusion and exclusion criteria, and addition of ANA testing.
    18 Jul 2012
    NB: Urgent Safety Measure In light of signals of liver toxicity being experienced by some patients, the DMC was convened. This toxicity was attributed to the PEG-Asparaginase (nIMP) component of the chemotherapy back bone. Committee recommended an USM be implemented which prescribes changes to the dose of PEG-Asparaginase (nIMP) based on patient disease status, age and any conmeds/comorbidity. These are summarised below: 2 doses of asparaginase – Day 4 and Day 18 • Patients who are being treated with curative intent - this will typically be younger, fitter patients in first relapse heading for an allograft procedure in CR2 • If patients in this group suffer >grade 2 liver toxicity after the first dose of asparaginase, the second dose, on Day 18, should be omitted. 1 dose of asparaginase – Day 18 • Those patients who do not fit into either above or below category, at physician’s discretion. 0 doses of asparaginase • Over 60 years of age. • Philadelphia positive on TKIs. • On third line therapy. • Have chronic/underlying liver co-morbidities, including but not limited to liver GVHD or a history of liver disease. • Grade 2 Baseline LFTs. To ensure that these safety measures are effective, mandated expedited reporting of all liver toxicity of grade 3 and grade 4 with a further review of safety data after 10 patients have been recruited to Cohort C of the trial.
    18 Jul 2012
    Urgent safety measure - changes to the dose of PEG-Asparaginase (NIMP) based on patient disease status, age and any concomitant medications/ co morbidity. The expedited reporting of all liver toxicity of grade 3 and grade 4 was additionally mandated in this amendment.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The MARALL Trial was terminated prematurely in October 2014 due to lack of veltuzumab supply from the manufacturer (Immunomedics) - it should be noted that the decision to stop supply was not related to drug safety or efficacy.
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